title: The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts.
abstract: Nonsyndromic orofacial clefts (OFC) are common birth defects caused by certain genes interacting with environmental factors. Mutations and association studies indicate that the homeobox gene MSX1 plays a role in human clefting. In a Dutch case-control triad study (mother, father, and child), we investigated interactions between MSX1 and the parents' periconceptional lifestyle in relation to the risk of OFC in their offspring. We studied 181 case- and 132 control mothers, 155 case- and 121 control fathers, and 176 case- and 146 control children, in which there were 107 case triads and 66 control triads. Univariable and multivariable logistic regression analyses were applied, and odds ratios (OR), 95% confidence intervals (CI) were calculated. Allele 4 of the CA marker in the MSX1 gene, consisting of nine CA repeats, was the most common allele found in both the case and control triads. Significant interactions were observed between allele 4 homozygosity of the child with maternal smoking (OR 2.7, 95% CI 1.1-6.6) and with smoking by both parents (OR 4.9, 95% CI 1.4-18.0). Allele 4 homozygosity in the mother and smoking showed a risk estimate of OR 3.2 (95% CI 1.1-9.0). If allele 4 homozygous mothers did not take daily folic acid supplements in the recommended periconceptional period, this also increased the risk of OFC for their offspring (OR 2.8, 95% CI 1.1-6.7). Our findings show that, in the Dutch population, periconceptional smoking by both parents interacts with a specific allelic variant of MSX1 to significantly increase OFC risk for their offspring. Possible underlying mechanisms are discussed.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. m.j.h.vandenboogaard@umcutrecht.nl
authors.forename: Marie-José H
authors.initials: MJ
authors.lastname: van den Boogaard
authors.forename: Dominique
authors.initials: D
authors.lastname: de Costa
authors.forename: Ingrid P C
authors.initials: IP
authors.lastname: Krapels
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.forename: Cock
authors.initials: C
authors.lastname: van Duijn
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sinke
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.forename: Régine P M
authors.initials: RP
authors.lastname: Steegers-Theunissen
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002971:Cleft Lip / Q000209:etiology* / Q000235:genetics*; D002972:Cleft Palate / Q000209:etiology* / Q000235:genetics*; D005260:Female; D005306:Fertilization; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D051957:MSX1 Transcription Factor / Q000235:genetics*; D008297:Male; D011247:Pregnancy; D012307:Risk Factors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D014028:Tobacco Smoke Pollution